Modulators of dopamine neurotransmission

ABSTRACT

New 3-substituted 4-(phenyl-N-alkyl)-piperazine and 4-(phenyl-N-alkyl)-piperidine compounds of Formula (1), wherein X N, CH, or C, however X may only be C when the compound comprises a double bond at the dotted line; R 1  is OSO 2 CF 3 , OSO 2 CH 3 , SOR 3 , SO 2 R 3 , COR 3 , NO 2 , or CONHR 3  and when X is CH or C R 1  may also be CF 3 , CN, F, Cl, Br, or I; R 2  is a C 1 -C 4  alkyl, an allyl, CH 2 SCH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 CH 2 F, CH 2 CF 3 , 3,3,3-trifluoropropyl, 4,4,4,-trifluorobutyl, or —(CH 2 )—R 4 ; R 3  is a C 1 -C 3  alkyl CF 3 , or N(R 2 ) 2 ; R 4  is a C 3 -C 6  cycloalkyl, 2-tetrahydrofurane or 3-tetra-hydrofurane, as well as pharmaceutically acceptable salts thereof are disclosed. Also pharmaceutical compositions comprising the above compounds and methods wherein the above compounds are used for treatment of disorders in the central nervous system are disclosed

This application is a 371 of PCT/SE00/02674, filed Dec. 22, 2000.

FIELD OF THE INVENTION

The present invention relates to new modulators of dopamineneurotransmission, and more specifically to new substituted 4-(phenylN-alkyl)-piperazines and 4-(phenyl N-alkyl)-piperidines, and usethereof.

BACKGROUND OF THE INVENTION

Dopamine is a neurotransmitter in the brain. Since this discovery, madein the 1950s, the function of dopamine in the brain has been intenselyexplored. To date, it is well established that dopamine is essential inseveral aspects of brain function including motor, cognitive, sensory,emotional and autonomous (e.g. regulation of appetite, body temperature,sleep) functions. Thus, modulation of dopaminergic function may bebeneficial in the treatment of a wide range of disorders affecting brainfunctions. In fact, both neurologic and psychiatric disorders aretreated with medications based on interactions with dopamine systems anddopamine receptors in the brain.

Drugs that act, directly or indirectly, at central dopamine receptorsare commonly used in the treatment of neurologic and psychiatricdisorders, e.g. Parkinson's disease and schizophrenia. Currentlyavailable dopaminergic pharmaceuticals have severe side effects, such asextrapyramidal side effects and tardive dyskinesia in dopaminergicantagonists used as antipsychotic agents, and dyskinesias and psychosesin dopaminergic agonists used as anti-Parkinson's agents. Therapeuticeffects are unsatisfactory in many respects. To improve efficacy andreduce side effects of dopaminergic pharmaceuticals, novel dopaminereceptor ligands with selectivity at specific dopamine receptor subtypesor regional selectivity are sought for. In this context, also partialdopamine receptor agonists, i.e. dopamine receptor ligands with some butnot full intrinsic activity at dopamine receptors, are being developedto achieve an optimal degree of stimulation at dopamine receptors,avoiding excessive dopamine receptor blockade or excessive stimulation.

Compounds belonging to the class of substituted4-(phenyl-N-alkyl)-piperazine and substituted4-(phenyl-N-alkyl)-piperidines have been previously reported. Amongthese compounds, some are inactive in the CNS, some display serotonergicor mixed serotonergic/dopaminergic pharmacological profiles while someare full or partial dopamine receptor agonists or antagonists with highaffinity for dopamine receptors.

A number of 4-phenylpiperazines and 4-phenylpiperidine derivatives areknown and described, for example Costall et al. European J. Pharm. 31,94, (1975), Mewshaw et al. Bioorg. Med. Chem. Lett., 8, 295, (1998). Thereported compounds are substituted 4-phenylpiperazine's, most of thembeing 2-, 3- or 4-OH phenyl substituted and displaying DA autoreceptoragonist properties.

Fuller R. W. et al, J. Pharmacol. Exp. Therapeut. 218, 636, (1981)disclose substituted piperazines (e.g.1-(m-trifluoro-methylphenyl)piperazine) which reportedly act asserotonin agonists and inhibit serotonin uptake. Fuller R. W. et al,Res. Commun. Chem. Pathol. Pharmacol. 17, 551, (1977) disclose thecomparative effects on the 3,4-dihydroxy-phenylacetic acid and Res.Commun. Chem. Pathol. Pharmacol. 29, 201, (1980) disclose thecomparative effects on the 5-hydroxyindole acetic acid concentration inrat brain by 1-(p-chlorophenol)-piperazine.

Boissier J. et al Chem Abstr. 61:10691c, disclose disubstitutedpiperazines. The compounds are reportedly adrenolytics,antihypertensives, potentiators of barbiturates, and depressants of thecentral nervous system.

A number of different substituted piperazines have been published asligands at 5-HT_(1A) receptors, for example Glennon R. A. et al J. Med.Chem., 31, 1968, (1988), van Steen B. J., J. Med. Chem., 36, 2751,(1993), Mokrosz, J. et al, Arch. Pharm. (Weinheim) 328, 143-148 (1995),and Dukat M.-L., J. Med. Chem., 39, 4017, (1996). Glennon R. A.discloses, in international patent applications WO 93/00313 and WO91/09594 various amines, among them substituted piperazines, as sigmareceptor ligands. Clinical studies investigating the properties of sigmareceptor ligands in schizophrenic patients have not generated evidenceof antipsychotic activity, or activity in any other CNS disorder. Two ofthe most extensively studied selective sigma receptor antagonists,BW234U (rimcazole) and BMY14802, have both failed in clinical studies inschizophrenic patients (Borison et al, 1991, Psychopharmacol Bull 27(2):103-106; Gewirtz et al, 1994, Neuropsychopharmacology 10:37-40).

Further, WO 93/04684 and GB 2027703 also describe specific substitutedpiperazines useful in the treatment of CNS disorders.

SUMMARY OF THE INVENTION

The object of the present invention is to provide new pharmaceuticallyactive compounds, especially useful in treatment of disorders in thecentral nervous system, which do not have the disadvantages of the abovedescribed substances.

In the work leading to the present invention, it was found that it isdesired to provide substances with specific pharmacological properties,namely substances that have modulating effects on dopamineneurotransmission. These properties have not been described earlier, andthey are not possible to obtain with the earlier known compounds. Thecompounds according to the present invention have a very surprising andinteresting dualistic dopaminergic action profile with antagonist-likeeffects on brain neurochemistry and mild agonist-like effects on normalbehavior, but they induce inhibition of behavior in states ofhyperactivity.

The present invention thus relates to new 3-substituted4-(phenyl-N-alkyl) piperazines and 3-substituted 4-(phenyl-N-alkyl)piperidines in the form of free base or pharmaceutically acceptablesalts thereof, pharmaceutical compositions containing said compounds anduse of said compounds in therapy.

One subject of the invention is to provide new compounds for therapeuticuse, and more precisely compounds for modulation of dopaminergic systemsin the mammalian brain, including human brain.

Another subject of the invention is to provide compounds withtherapeutic effects after oral-administration.

More precisely, the present invention relates to 3-substituted 4-(phenylN-alkyl)-piperazine and 4-(phenyl-N-alkyl)-piperidine compounds ofFormula 1:

and pharmaceutically acceptable salts thereof, wherein:

-   X is selected from the group consisting of N, CH, and C, however X    may only be C when the compound comprises a double bond at the    dotted line;-   R₁ is selected from the group consisting of OSO₂CF₃, OSO₂CH₃, SOR₃,    SO₂R₃, COR₃, NO₂, and CONHR₃, wherein R₃ is as defined below, and    when X is CH or C R₁ may also be selected from the group consisting    of CF₃, CN, F, Cl, Br, and I;-   R₂ is selected from the group consisting of C₁-C₄ alkyls, allyls,    CH₂SCH₃, CH₂CH₂OCH₃, CH₂CH₂CH₂F, CH₂CF₃, 3,3,3-trifluoropropyl,    4,4,4-trifluorobutyl, and —(CH₂)—R₄, wherein R₄ is as defined below;-   R₃ is selected from the group consisting of C₁-C₃ alkyls, CF₃, and    N(R₂)₂, wherein R₂ is as defined above;-   R₄ is selected from the group consisting of C₃-C₆ cycloalkyls,    2-tetrahydrofurane and 3-tetra-hydrofurane.

The compounds according to the present invention possessdopamine-modulating properties and are useful in treating numerouscentral nervous system disorders including both psychiatric andneurological symptoms.

Diseases in which compounds with modulating effects on dopaminergicsystems may be beneficial are in disorders related to ageing, forpreventing bradykinesia and depression and for the improvement of mentalfunctions. They may also be used to improve cognitive functions andrelated emotional disturbances in neurodegenerative and developmentaldisorders as well as after brain damage.

The compounds according to the invention can be used to improve allsymptoms of psychosis, including schizophrenia and schizophreniformdisorders as well as drug induced psychotic disorders. The compoundsaccording to the invention may also be used in behavioral disordersusually first diagnosed in infancy, childhood, or adolescence as well asin impulse control disorders. Also, speech disorders such as stutteringmay improve. They may also be used for treating substance abusedisorders as well as disorders characterized by misuse of food.

Mood and anxiety disorders, personality disorders, and conversionhysteria may also be treated with the compounds according to theinvention.

Neurological indications include the treatment of Huntington's diseaseand other movement disorders as well as movement disorders induced bydrugs. Restless legs and related disorders as well as narcolepsy mayalso be treated with compounds included according to the invention. Theymay also improve mental and motor function in Parkinson's disease, andin related parkinsonian syndromes. They may also be used to amelioratetremor of different origins. They may be used in the treatment ofheadaches and used to improve brain function following vascular ortraumatic brain injury. Moreover, they may be used to relieve pain inconditions characterized by increased muscle tone.

The compounds according to the present invention have unexpectedly beenfound to act specifically on dopaminergic systems in the brain. Theyhave effects on biochemical indices in the brain with the characteristicfeatures of selective dopamine antagonists, e.g. producing increases inconcentrations of dopamine metabolites.

Yet, dopamine receptor antagonists characteristically suppressbehavioral activity and induce catalepsy, while the compounds of thisinvention show no, or only limited, inhibitory effects on spontaneouslocomotion. In contrast they may induce a slight behavioral activationwith concomitant increases in small-scale movements, e.g. stops in thecenter of the behavior recording arena, similar to that induced bydopaminergic agonists. The behavioral activation is limited, notreaching the profound increases in activity induced by direct orindirect dopaminergic agonists. On the other hand, the preferredsubstances reduce the increase in activity induced by direct or indirectdopaminergic agonists, i.e. d-amphetamine and congeners.

Thus, the compounds of this invention surprisingly show an interestingdualistic dopaminergic action profile with antagonist like effects onbrain neurochemistry and mild agonist like effects on normal behavior,but inhibition of behavior in states of hyperactivity. The actionprofile suggests modulatory effects on dopaminergic functions, clearlydifferent from known compounds belonging to these chemical classes oreffects anticipated of typical dopamine receptor antagonists or agonistsfrom these or other chemical classes.

Given the involvement of dopamine in a large variety of CNS functionsand the clinical shortcomings of presently available pharmaceuticalsacting on dopamine systems, the novel class of dopaminergic modulatorspresented in this invention may prove superior to presently knowndopaminergic compounds in the treatment of several disorders related todysfunctions of the CNS, in terms of efficacy as well as side effects.

Some compounds according to the invention have been found to havesurprisingly good pharmacokinetic properties including high oralbioavailability. They are thus suitable for the preparation of orallyadministered pharmaceuticals. There is no guidance in the prior art howto obtain compounds with this effect on dopamine systems in the brain.

DETAILED DESCRIPTION OF THE INVENTION

Pharmacology

Evidence is available that neurotransmission in the CNS is disturbed inpsychiatric and neurologic diseases. In many instances, for example inschizophrenia or Parkinson's disease, pharmacotherapies based onantagonism or agonism at dopamine receptors are useful, but not optimal.In recent years much efforts have been put on finding novel andselective ligands for dopamine receptor subtypes (D₁, D₂, D₃, D₄, D₅)with the aim to improve efficacy and reduce side effects.

The present invention offers another principle for novel therapeuticsbased on interactions with dopamine systems. The compounds according tothe invention have effects on brain neurochemistry similar toantagonists at dopamine D₂ receptors. In contrast to currently useddopamine receptor antagonists the compounds according to the inventionshow no or limited inhibitory effects on spontaneous locomotion. Theymay induce behavioral activation with concomitant increases insmall-scale movements, e.g. stops in the center of the behaviorrecording arena, similar to that induced by dopaminergic agonists. Thebehavioral activation is limited, not reaching the profound increases inactivity induced by direct or indirect dopamine receptor agonists.Surprisingly, the preferred substances can actually reduce the increasein activity induced by direct or indirect dopaminergic agonists, i.e.d-amphetamine and congeners.

The preferred structures are substituted in the meta position on thearomatic ring. An example of such a compound is methanesulfonic acid3-(1-propyl-piperidin-4-yl)-phenyl ester, which is shown in Example 14below. In rat, this compound increases 3,4-dihydroxyphenylacetic acid inthe striatum from 1265±74 (controls) to 3208±236 ng/g tissue at 50μmol/kg s.c. in combination with a slight increase in behavioralactivity; 1485±328 cm/30 min (controls) to 2126±240 cm/30 min at 50μmol/kg s.c., n=4. Another preferred example of a compound according tothe invention is 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine,further illustrated in Example 6. In rat, this compound increases3,4-dihydroxy-phenylacetic acid in the striatum from 914±19 (controls)to 1703±19 ng/g tissue at 50 μmol/kg s.c. This increase in dopamineturnover is followed by a trend towards an increase in motor activityfrom 2030±299 cm/60 min to 2879±398 cm/60 min p=0.14. In animalshabituated to the motilitymeter box the compound described in Example 6,4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine, increases behavioralactivity from 476±279 cm/60 min (controls) to 1243±72 cm/60 min, p<0.05,n=4, and 4-dihydroxyphenylacetic acid in the striatum from 975±23(controls) to 2074±144 ng/g tissue at 50 μmol/kg s.c., p<0.05, n=4.

In addition, the compound described in Example 6,4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine, has the preferredability to reduce behavioral activation induced by both d-amphetamine(1.5 mg/kg s.c.) and dizolcipine (Mk-801, 0, 7 mg/kg i.p.).d-Amphetamine hyperactivity is reduced from 10694±2165 cm/60 min to1839±344 cm/60min, p<0.05 n=4, at 50 μmol/kg s.c. of the compounddescribed in Example 6 and behavioral activation induced by dizolcipine(Mk-801) is reduced from 32580±4303 cm/60 min to 18197±1389 cm/60 minp<0.05, at 50 μmol/kg sc. Surprisingly, the compound described inExample 6 has an oral availability (F) of 85% in rat.

Unlike the somewhat similar compounds described in WO91/09594, thecompound of Example 6,4-(3-methane-sulfonyl-phenyl)-1-propyl-piperidine, lacks affinity at thesigma receptor, <50% inhibition of [³H]-DTG binding (according to amethod for measurement of sigma binding described by Shirayama Y. etal., 1993, Eur. J. Pharmacol. 237, p 117) at 10 μmol/L to rat brainmembranes.

In order to demonstrate the surprising effects of the compoundsaccording to the invention, some of the compounds have been compared tosimilar compounds according to prior art. The compounds-used forcomparison with the compounds according to the invention in thecomparative examples are thus not compounds according to the inventionsince they do not exhibit the desired properties.

COMPARATIVE EXAMPLE 1

4-(4-methanesulphonyl-phenyl)-1-propyl piperidine illustrates thatsubstitution in the para position yields inactive compounds.4-(4-methanesulphonyl-phenyl)-1-propyl piperidine has no effect on3,4-dihydroxyphenyl-acetic acid in the striatum as demonstrated in theneurochemical experiment; 988±70 (controls) ng/g tissue and 928±51 ng/gtissue at 50 μmol/kg s.c. 4-(4-methanesulphonyl-phenyl)-1-propylpiperidine does not have the properties desired according to theinvention.

COMPARATIVE EXAMPLE 2

To further illustrate the importance of the substitition on the aromaticring for the desired properties, 4-phenyl-1-propyl-piperidine isdemonstrated to lack activity in the behavioral assay in thenon-pre-treated rat, 3661±494 cm/60 min, controls, to 2553±471 cm/60min, p>0.05, n=4, at 33 μmol/kg and lacks effects on3,4-dihydroxyphenyl-acetic acid in the striatum as demonstrated in theneurochemical experiment; 1027±31 (controls) ng/g tissue and 1190±70ng/g tissue at 33 μmol/kg s.c., p>0.05., 4-phenyl-1-propyl-piperidine]also lacks the desired inhibition of behavioral activity in thed-amphetamine stimulated (17295±4738 cm/60 min, d-amphetamine, to13764±2919 cm/60 min, n=4, p>>0.05 at 33 μmol/kg.

COMPARATIVE EXAMPLE 3

Further, 1-phenyl-4-propyl-piperazine, described as sigma receptorbinding compound in WO91/09594, is found to reduce behavioral activityin the non-pre-treated animal, from 3370±227, controls, to 1923±204cm/60 min, n=4, p<0.05 at 33 μmol/kg s.c., thus lacking the propertiessought for.

COMPARATIVE EXAMPLE 4

Substitution in the ortho position as exemplified by1-(2-methoxy-phenyl)-4-propyl piperazine yields a compound whichincreases 3,4-dihydroxyphenylacetic acid in the striatum from 1028±9(controls) ng/g tissue to 3836±65 ng/g tissue at 50 μmol/kg s.c.,p<0.05, n=4. This is followed by the behavioral inhibition not soughtfor in the present invention; 1651±300 cm/60 min (controls) to 67±34cm/60 min, at 50 μmol/kg s.c., p<0.05, n=4.

COMPARATIVE EXAMPLE 5

The properties of the substituent in the meta position are important.1-propyl-4-(3-triflouro-methyl-phenyl) piperazine increases3,4-dihydroxyphenyl-acetic acid in the striatum from 1066±46 (controls)ng/g tissue to 3358±162 ng/g tissue at 50 μmol/kg s.c., p<0.05, n=4,however, followed by behavioral inhibition from 1244±341 cm/60 min(controls) to 271±137 at 50 μmol/kg s.c., p<0.05, n=4, thus, lacking theproperties sought for in the present invention.

COMPARATIVE EXAMPLE 6

Further, the compound of 3-(4-Propyl-piperazine-1-yl)-benzonitrileincreases 3,4-dihydroxyphenyl-acetic acid in the striatum from 1432±57(controls) ng/g tissue to 4498±243 ng/g tissue at 100 μmol/kg s.c.,p<0.05, n=4, and reduces 5-hydroxy-indole acetic acid from 630±16(controls) ng/g tissue to 484±26 ng/g tissue at 100 μmol/kg s.c.,p<0.05, n=4. These effects are followed by behavioral inhibition from3959±688 cm/60 min (controls) to 634±266 at 100 μmol/kg s.c., p<0.05,n=4, thus, lacking the properties sought for in the present invention.3-(4-Propyl-piperazine-1-yl)-benzonitrile has the following properties:m.p. 159° C. (fumarate) MS m/z (relative intensity, 70 eV) 229 (M+, 28),200 (bp), 157 (27), 129 (22), 70 (25).

COMPARATIVE EXAMPLE 7

Another example of the importance of the substituent is preparation 14which has no effect on 3,4-dihydroxy-phenyl-acetic acid in the striatum;1121±36 (controls) ng/g tissue to 1169±42 ng/g tissue at 50 μmol/kg s.c.

COMPARATIVE EXAMPLE 8

The physicochemical properties of the substituent on the basic nitrogenis also important for the desired profile. It is not possible to use anysubstituent, which is exemplified by1-phenethyl-4-(3-trifluoromethyl-phenyl)-piperazine described as a sigmareceptor ligand in WO 91/09594 and WO 93/00313 which has some effects on3,4-dihydroxyphenylacetic acid in the striatum; 852±33 (controls) to1406±77 ng/g tissue at 50 μmol/kg s.c., p<0.05, n=4, but also reducesboth 5-hydroxyindoleacetic acid in the striatum from 358±20 (controls)to 289±16 ng/g tissue at 50 μmol/kg s.c., p<0.05, n=4, and serotonin(5-HT) from 379±10 (controls) to 282±6 ng/g tissue at 50 μmol/kg s.c.,p<0.05, n=4, which is an undesired property according to this inventionbut in accordance with the reported IC50 of 20,3 nM at the 5-HT_(1A)receptor (WO 93/00313).

COMPARATIVE EXAMPLE 9

In addition, 1-benzyl-4-(3-methanesulfonyl-phenyl)-piperidine and3-(1-benzyl-piperidin-4-yl)-phenol, compounds with benzylic substitutionon the basic nitrogen, both has the undesired property to interact withserotonin systems in the brain.1-Benzyl-4-(3-methanesulfonyl-phenyl)-piperidine increases5-hydroxyindoleacetic acid in the striatum from 428±20 (controls) to487±7 ng/g tissue at 50 μmol/kg s.c., p<0.05, n=4, and reduces serotonin(5-HT) from 442±15 (controls) to 345±18 ng/g tissue at 50 μmol/kg s.c.,p<0.05, n=4, and induces the serotonin behavioral syndrome (serotoninbehavioral syndrome is e.g. described by Tricklebank et al., 1985, Eur.J. Pharmacol, 106, pp 271-282). 3-(1-Benzyl-piperidin-4-yl)-phenol hasthe undesired ability to increse 5-hydroxyindoleacetic acid in thestriatum from 404±10 (controls) to 492±26 ng/g tissue at 50 μmol/kgs.c., p<0.05, n=4, and reduces serotonin in the limbic region (5-HT)from 734±8 (controls) to 677±20 ng/g tissue at 50 μmol/kg s.c., p<0.05,n=4.

COMPARATIVE EXAMPLE 10

Substitution on the basic nitrogen according to2-[4-(3-methanesulfonyl-phenyl)-piperazin-1-yl]-ethanol] (described inGB 2027703) renders compounds which are inactive in the behavioralactivity test; 3238±1089 cm/60 min (controls) to 3782±962 cm/60 min at33 μmol/kg s.c., n=4, p>0.05, as well as in the neurochemical test;effects on 3,4-dihydroxyphenylacetic acid in the striatum; 1158±126(controls) to 1239±162 ng/g tissue at 33 μmol/kg s.c., n=4, p>0.05.

The compounds according to the invention are especially suitable fortreatment of disorders in the central nervous system, and particularlyfor treatment of dopamine mediated disorders. They may, e.g. used toameliorate symptoms of mood disorders, in obesitas as an anorectic agentand in other eating disorders, to improve cognitive functions andrelated emotional disturbances, to improve cognitive and motordysfunctions associated with developmental disorders, to improve allsymptoms of schizophrenia and schizophreniform disorders as well asother psychoses, to improve ongoing symptoms as well as to prevent theoccurrence of new psychotic episodes, to regulate pathological disordersdue to intake of food, coffee, tea, tobacco, alcohol, addictive drugsetc.

The compounds according to the invention can thus be used to treatsymptoms in e.g.:

-   -   schizophrenia and other psychotic disorders, such as catatonic,        disorganized, paranoid, residual or differentiated        schizophrenia; schizophreniform disorder; schizoaffective        disorder; delusional disorder; brief psychotic disorder; shared        psychotic disorder; psychotic disorder due to a general medical        condition with delusions and/or hallucinations;    -   mood disorders, such as depressive disorders , e.g., dysthymic        disorder or major depressive disorder; bipolar disorders, e.g.,        bipolar I disorder, bipolar II disorder, and cyclothymic        disorder; mood disorder due to a general medical condition with        depressive, and/or manic features; and substance-induced mood        disorder;    -   anxiety disorders, such as acute stress disorder, agoraphobia        without history of panic disorder, anxiety disorder due to        general medical condition, generalized anxiety disorder,        obsessive-compulsive disorder, panic disorder with agoraphobia,        panic disorder without agoraphobia, posttraumatic stress        disorder, specific phobia, social phobia, and substance-induced        anxiety disorder;    -   eating disorders, such as anorexia nervosa, bulimia nervosa, and        obesitas;    -   sleep disorders, such as dyssomnias, e.g., breathing-related        sleep disorder, circadian rhythm sleep disorder, hypersomnia,        insomnia, narcolepsy, and “jet lag”;    -   impulse-control disorders not elsewhere classified, such as        intermittent explosive disorder, kleptomania, pathological        gambling, pyromania, and trichotillomania;    -   personality disorders, such as paranoid, schizoid or schizotypal        disorder; antisocial, borderline, histrionic, and narcissistic        disorder; and avoidant, dependent, obsessive-compulsive        disorder;    -   medication-induced movement disorders, such as neuroleptic        induced parkinsonism, neuroleptic malignant syndrome,        neuroleptic induced acute and tardive dystonia, neuroleptic        induced akathisia, neuroleptic induced tardive dyskinesia,        medication induced tremor, and medication induced dyskinesias;    -   substance-related disorders, such as abuse, dependence, anxiety        disorder, intoxication, intoxication delirium, psychotic        disorder, psychotic disorder with delusions, mood disorder,        persisting amnestic disorder, persisting dementia, persisting        perception disorder, sexual dysfunction, sleep disorder,        withdrawal, and withdrawal delirium due to use ore misuse of        alcohol, amphetamine (or amphetamine-like substances), caffeine,        cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids,        phencyclidine (or phencyclidine-like substances), sedative        substances, hypnotic substances, and/or anxiolytic substances;    -   disorders usually first.diagnosed in infancy, childhood, or        adolescence, such as mental retardation; learning disorders;        motor skills disorders, e.g. developmental coordination        disorder; communication disorders, e.g. expressive language        disorder, phonological disorder, receptive-expressive language        disorder and stuttering; pervasive developmental disorders, e.g.        Asperger's disorder, autistic disorder, childhood disintegrative        disorder, and Rett's disorder; attention-deficit and disruptive        behavior disorders, e.g. attention-deficit/hyperactivity        disorder, conduct disorder, and oppositional defiant disorder;        feeding and eating disorders of infancy or early childhood, e.g.        feeding disorder of infancy or early childhood, pica, rumination        disorder; tic disorders, e.g. chronic motor or vocal tic        disorder, and Tourette's disorder; other disorders of infancy,        childhood, or adolescence, e.g. selective mutism, and        stereotypic movement disorder;    -   delirium, dementia, amnestic and other cognitive disorders, such        as Alzheimer's, Creutzfeldt-Jakob disease, dead trauma,        Huntington's disease, HIV disease, Pick's disease, and diffuse        Lewy body dementia;    -   conversion hysteria;    -   conditions connected to normal aging, such as disturbances in        motor functions and mental functions;    -   Parkinson's Disease and related disorders, such as multiple        system atrophies, e.g. striatonigral degeneration,        olivopontocerebellar atrophy, and shydrager syndrome;        progressive supranuclear palsy; corticobasal degeneration; and        vascular parkinsonism;    -   tremors, such as essential, orthostatic, rest, cerebellar, and        secondary tremor    -   headaches, such as migraine, cluster headache, tension type        headache, and paroxysmal headache;    -   movement disorders, such as dyskinesias, e.g. in deneral        medicine condition, secondary to trauma or vascular insult,        hemiballism, athetosis, Sydenham's chorea, and paroxyssmal;        dystonias; Ekbom's syndrome (restless legs); Wilson's Disease;        Hallerworden-Spatz disease;    -   rehabilitation medicine, e.g. to improve rehabilitation after        vascular or traumatic brain injury;    -   pain in conditions characterized by increased muscular tone,        such as fibromyalgia, myofascial syndrome, dystonia, and        parkinsonism; as well as    -   conditions related to the above that fall within the larger        categories but does not meet the criteria of any specific        disorder within those categories.        Synthesis

The synthesis of the present compounds is carried out by methods thatare conventional for the synthesis of related known compounds. Thesyntheses of compounds in Formula 1, in general, comprise the reactionof an intermediate that supplies the alkyl group with an intermediatepiperidine or piperazine that supplies the amine group of Formula 2:

A convenient method of synthesis of the present compounds is by use ofan alkyl iodide (e.g. 1-propyl-iodide). Alternatively, other leavinggroups besides iodide may be used on the alkyl group, of course, such assulfonates, particularly methanesulfonate or toluenesulfonate, bromo andthe like. The alkyl intermediate is reacted with the appropriate aminein the presence of any convenient acid scavenger. The usual bases suchas alkali metal or alkaline earth metal carbonates, bicarbonates andhydroxides are useful acid scavengers, as are some organic bases such astrialkylamines and trialkanolamines. The reaction medium for suchreactions may be any convenient organic solvent which is inert to thebasic conditions; acetonitrile, esters such as ethylacetate and the likeand halogenated alkane solvents are useful. Usually the reactions willbe carried out at elevated temperatures such as from ambient temperatureto the reflux temperature of the reaction mixture, particularly from 50°C. to about 100° C.

Another convenient method of synthesis of the present compounds involvesreductive amination with an amine of Formula 2:

with an aldehyde or ketone, either in the presence of a reducing agentsuch as sodium cyanoborohydride or sodium triacetoxyborohydride orfollowed by reduction, e.g. using catalytic hydrogenation, to give acorresponding compound of Formula 1.

Compounds of Formula 3

wherein X═N is accomplished by reacting compounds of Formula 4:

with compounds of Formula 5:

where Z is a leaving group like iodide. Other leaving groups besidesiodide may be used on the alkyl group, of course, such as sulfonates,particularly methanesulfonate or toluenesulfonate, bromo and the like.The alkyl intermediate is reacted with the appropriate amine in thepresence of any convenient acid scavenger. The usual bases such asalkali metal or alkaline earth metal carbonates, bicarbonates andhydroxides are useful acid scavengers, as are some organic bases such astrialkylamines and trialkanolamines. The reaction is performed in asuitable solvent such as n-butanol by heating at about 50-150° C.

Compounds of the Formula 1 wherein X═N is also accomplished by reactingcompounds of Formula 6:

with an aryl substituted with a leaving group of Formula 7:

where Z is halide e.g. chloro, bromo, iodo, or sulfonate e. g. —OSO₂CF₃,or —OSO₂F, in the presence of a base and a zerovalent transition metalcatalyst such as Pd or Ni, according to known method (TetrahedronLetters, vol 37, 1996, 4463-4466, J. Org. Chem., vol. 61, 1996,1133-1135).

The catalyst, preferably Pd will have the ability to form ligand complexand undergo oxidative addition. Typical Pd catalysts will be Pd₂(dba)₃(wherein dba refers to di-benzylidene acetone), Pd(PPh₃)₄, Pd(OAc)₂, orPdCl₂[P(o-tol)₃]₂ and typical phosphine ligands will be BINAP,P(o-tol)₃, dppf, or the like. The usual bases such as alkali metal oralkaline earth metal carbonates, bicarbonates and alkyloxides are usefulacid scavengers, as are some organic bases such as trialkylamines andtrialkanolamines. The reaction medium for such reactions may be anyconvenient organic solvents, which are inert to the basic conditions;acetonitrile, toluene, dioxane, NMP (N-methyl-2-pyrrolidone), DME(dimethoxyethane), DMF (N,N-dimethylformamide), DMSO (dimethylsulfoxide)and THF (tetrahydrofuran) solvents are useful. Usually the reactionswill be carried out at elevated temperatures such as from ambienttemperature to the reflux temperature of the reaction mixture,particularly from 50° C. to about 120° C.

Compounds of the Formula 1 wherein X═N is also accomplished by reactingcompounds of Formula 6 with an aryl substituted with a leaving group(e.g. F or Cl) via nucleophilic aromatic displacement reactions in thepresence of a base as explained above.

Compounds of the Formula 1 wherein X═CH is also accomplished bytransition metal catalyzed cross-coupling reaction, known as, forexample, Suzuki and Stille reactions, to those skilled in the art.The reaction may be carried out between compounds of Formula 8:

wherein Y is, for example, a dialkylborane, dialkenylborane or boronicacid (e.g. BEt₂, B(OH)₂ (dotted lines can be double bonds)) or atrialkyltin (e.g. SnMe₃, SnBu₃), and an aryl substituted with a leavinggroup of Formula 7:

(for definition of Z, see above) in the presence of a base and azerovalent transition metal catalyst such as Pd or Ni, according toknown methods (Chem. Pharm. Bull., vol 33, 1985, 4755-4763, J. Am. Chem.Soc., vol. 109, 1987, 5478-5486., Tetrahedron Lett., vol. 33, 1992,2199-2202). In addition, Y can also be a zink- or magnesium-halide group(e.g. ZnCl₂, ZnBr₂, ZnI₂, MgBr₂, MgI₂) according to known methods(Tetrahedron Lett., vol. 33, 1992, 5373-5374, Tetrahedron Lett., vol.37, 1996, 5491-5494).

The catalyst, preferably Pd will have the ability to form ligand complexand undergo oxidative addition. The definition of ligands, bases andsolvents, is mentioned above.

Alternatively, the transition metal catalyzed cross-coupling reactioncan be performed with the opposite substitution pattern:

with an heteroaryl/alkenyl substituted with an leaving group of Formula10:

in the presence of a base and a zerovalent transition metal catalystsuch as Pd or Ni, according known methods discussed in the previousparagraph.

Compounds of Formula 11:

can be prepared by catalytic hydrogenation of the tetrahydropyridine orpyridine from the previous paragraph, using standard methods known inthe art, generally with palladium on carbon, PtO2, or Raney nickel asthe catalyst. The reaction is performed in an inert solvent, such asethanol or ethyl acetate, either with or without a protic acid, such asacetic acid or HCl. When the pyridine ring is quaternized with an alkylgroup the ring can be partly reduced by NaBH₄ or NaCNBH₄, yielding thetetrahydropyridine analog which can further be reduced with catalytichydrogenation.

Another convenient method of syntheses of compounds of the Formula 1,wherein X═CH is also accomplished by treating arylhalides of Formula 7:

wherein Z is Cl, Br, or I, with alkyllithium reagents, for example,butyllithium, sec-butyllithium or tert-butyl-lithium, preferablybutyllitium or Mg (grignard reaction) in an inert solvent. Suitablesolvents include, for example ether or tetrahydrofuran, preferablytetrahydrofuran. Reaction temperatures range from about −110° C. toabout 60° C. The intermediate lithium anions or magnesium anions thusformed may then be further reacted with a suitable electrophile ofFormula 12:

wherein A is defined as a protecting group like t-Boc(tert-butoxycarbonyl), Fmoc (fluorenylmethoxycarbonyl), Cbz(benzyloxycarbonyl) or a an alkylgroup like benzyl. The intermediates ofFormula 13:

which are formed require that the hydroxy group be removed so as toresult in compounds of Formula 1 (X═CH).

This step may be accomplished by one of several standard methods knownin the art. For example, a thiocarbonyl derivative (for example axanthate) may be prepared and removed by a free radical process, ofwhich are known to those skilled in the art. Alternatively, the hydroxylgroup may be removed by reduction with a hydride source such astriethylsilane under acidic conditions, using such as, for example,trifluoroacetic acid or boron trifluoride. The reduction reaction can beperformed neat or in a solvent, such as methylene chloride. A furtheralternative would be to first convert the hydroxyl group to a suitableleaving group, such as tosylate or chloride, using standard methods. Theleaving group is then removed with a nucleophilic hydride, such as, forexample, lithium aluminium hydride. This last reaction is performedtypically in an inert solvent, such as, ether or tetrahydrofuran.

Another alternative method for removing the hydroxyl group is to firstdehydrate the alcohol to an olefin with a reagent such as Burgess salt(J. Org. Chem., vol 38, 1973, 26) followed by catalytic hydrogenation ofthe double bond under standard conditions with a catalyst such aspalladium on carbon. The alcohol may also be dehydrated to the olefin bytreatment with acid such as p-toluenesulfonic acid or trifluoroaceticacid.

The protecting group, A, is removed under standard conditions known bythose skilled in the art. For example, t-Boc cleavages are convenientlycarried out with trifluoroacetic acid either neat or in combination withmethylene chloride. F-moc is conveniently cleaved off with simple basessuch as, ammonia, piperidine, or morpholine, usually in polar solventssuch as DMF and acetonitrile. When A is Cbz or benzyl, these areconveniently cleaved off under catalytic hydrogenation conditions. Thebenzyl group can also be cleaved off under N-dealkylation conditionssuch as treatment with α-chloroethyl chloroformate (J. Org. Chem., vol49, 1984, 2081-2082).

It is further possible to convert a radical R₁ in a compound of theFormula 1 into another radical R₁, e.g. by oxidizing methylsulfide tomethylsulfone (for example by m-chloroperoxybenzoic acid), substitutionof a triflate or halide group with a cyano group (for example palladiumcatalyzed cyanation), substitution of triflate or halide group with aketone (for example palladium catalyzed Heck reaction with butyl vinylether), substitution of a triflate or halide group with a carboxamide(for example, palladium catalyzed carbonylation), or cleaving an etherby, for example, converting a methoxy group into the correspondinghydroxyl derivate, which can further be converted into the correspondingmesylate or triflate. The terms mesylate andtriflate refers to OSO₂CH₃,CH₃SO₃ or OSO₂CF₃, CF₃SO₃, respectively.

In summary, the general process for preparing the present compounds hassix main variations, which may briefly bedescribed as follows:

As used herein the term C₁-C₄ alkyl refers to an alkyl containing 1-4carbon atoms in any isomeric form. The various carbon moieties aredefined as follows: Alkyl refers to an aliphatic hydrocarbon radical andincludes branched or unbranched forms such as methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl. The term cycloalkyl refersto a radical of a saturated cyclic hydrocarbon such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl.

The term “patient” used herein refers to an individual in need of thetreatment according to the invention.

The term “treatment” used herein relates to both treatment in order tocure or alleviate a disease or a condition, and to treatment in order toprevent the development of a disease or a condition. The treatment mayeither be performed in an acute or in a chronic way.

Both organic and inorganic acids can be employed to form non-toxicpharmaceutically acceptable acid addition salts of the compoundsaccording to the invention. Illustrative acids are sulfuric, nitric,phosphoric, hydrochloric, citric, acetic, lactic, tartaric, palmoic,ethane disulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric,maleic, and benzoic acid. These salts are readily prepared by methodsknown in the art.

The pharmaceutical composition containing a compound according to theinvention may also comprise substances used to facilitate the productionof the pharmaceutical preparation or the administration of thepreparations. Such substances are well known to people skilled in theart and may for example be pharmaceutically acceptable adjuvants,carriers and preservatives.

In clinical practice the compounds used according to the presentinvention will normally be administered orally, rectally, or byinjection, in the form of pharmaceutical preparations comprising theactive ingredient either as a free base or as a pharmaceuticallyacceptable non-toxic, acid addition salt, such as the hydrochloride,lactate, acetate, sulfamate salt, in association with a pharmaceuticallyacceptable carrier. The carrier may be a solid, semisolid or liquidpreparation. Usually the active substance will constitute between 0.1and 99% by weight of the preparation, more specifically between 0.5 and20% by a weight for preparations intended for injection and between 0.2and 50% by weight for preparations suitable for oral administration.

To produce pharmaceutical preparations containing the compound accordingto the invention in the form of dosage units for oral application, theselected compound may be mixed with a solid excipient, e.g. lactose,saccharose, sorbitol, mannitol, starches such as potato starch, cornstarch or amylopectin, cellulose derivatives, a binder such as gelatineor polyvinyl-pyrrolidine, and a lubricant such as magnesium stearate,calcium stearate, polyethylene glycol, waxes, paraffin, and the like,and then compressed intotablets. If coated tablets are required, thecores, prepared as described above, may be coated with a concentratedsugar solution which may contain e.g. gum arabic, gelatine, talcum,titanium dioxide, and the like. Alternatively, the tablet can be coatedwith a polymer known to the man skilled in the art, dissolved in areadily volatile organic solvent or mixture of organic solvents.Dyestuffs may be added to these coatings in order to readily distinguishbetween tablets containing different active substances or differentamounts of the active compound.

For the preparation of soft gelatine capsules, the active substance maybe admixed with e.g. a vegetable oil or poly-ethylene glycol. Hardgelatine capsules may contain granules of the active substance usingeither the mentioned excipients for tablets e.g. lactose, saccharose,sorbitol, mannitol, starches (e.g. potato starch, corn starch oramylopectin), cellulose derivatives or gelatine. Also liquids orsemisolids of the drug can be filled into hard gelatine capsules.

Dosage units for rectal application can be solutions or suspensions orcan be prepared in the form of suppositories comprising the activesubstance in a mixture with a neutral fatty base, or gelatine rectalcapsules comprising the active substance in admixture with vegetable oilor paraffin oil. Liquid preparations for oral application may be in theform of syrups or suspensions, for example solutions containing fromabout 0.2% to about 20% by weight of the active substance hereindescribed, the balance being sugar and mixture of ethanol, water,glycerol and propylene glycol. Optionally such liquid preparations maycontain coloring agents, flavoring agents, saccharine andcarboxymethylcellulose as a thickening agent or other excipients knownto the man in the art.

Solutions for parenteral applications by injection can be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substance, preferably in a concentration of from 0.5% toabout 10% by weight. These solutions may also containing stabilizingagents and/or buffering agents and may conveniently be provided invarious dosage unit ampoules. The use and administration to a patient tobe treated in the clinic would be readily apparent to an ordinary skillin the art.

In therapeutical treatment an effective amount or a therapeutic amountof the compounds according to the invention are from about 0.01 to about500 mg/kg body weight daily, preferably 0.1-10 mg/kg body weight daily.The compounds may be administered in any suitable way, such as orally orparenterally. The daily dose will preferably be administered inindividual dosages 1 to 4 times daily.

It is known for those skilled in the art that replacing a hydrogen in anon-substituted position in the aromatic ring with a fluorine atom mayblock the possibility for enzymatic hydroxylation which render thecompound low oral bioavailability. This type of exchange (H to F) seldomchanges the pharmacological profile. Thus, it may be important, in somecases to introduce a fluorine atom in any non-substituted positions inthe aromatic ring of compounds of Formula 1 to improve the oralbioavailability.

The invention is further illustrated in the examples below, which in noway are intended to limit the scope of the invention.

EXAMPLE 1 1-(3-Methanesulfonyl-phenyl)-4-propyl-pierazine

A suspension of 1-(3-methanesulfonyl-phenyl)-piperazine (350 mg) andground K₂CO₃ (403 mg) was stirred in CH₃CN (25 mL) at room temperature.1-Iodo-propane (712 μL) was added. The mixture was refluxed overnight.The reaction mixture was filtered and the volatiles were evaporated invacuum. The oily residue was chromatographed on a silica column withMeOH:CH₂Cl₂ (1:30 (v/v)) as eluent. Collection of the fractionscontaining pure product and evaporation of the solvent afforded pure1-(3-methanesulfonyl-phenyl)-4-propyl-piperazine (220 mg). The amine wasconverted into the HCl salt and recrystallized fromethanol/diethylether: m.p. 233° C. MS m/z (relative intensity, 70 eV)282 (M⁺, 30), 254 (15), 253 (bp), 210 (17), 70 (21).

The following compounds according to Examples 2-11 were prepared in amanner similar to the one described in Example 1.

EXAMPLE 2 1-Propyl-4-(3-Trifluoromethanesulfonyl-phenyl)-piperazine

MS m/z (relative intensity, 70 eV) 336 (M+, 16), 307 (bp), 77 (18), 70(38), 56 (23).

EXAMPLE 3 1-[3-(4-Propyl-piperazin-1-yl)-phenyl]-ethanone

Beginning with 1-(3-Piperazin-1-yl-phenyl)-ethanone and n-Pr-I: m.p.119° C. (oxalate), MS m/z (rel. intensity, 70 eV) 246 (M+, 10), 217(33), 132 (18), 70 (bp), 56 (41); Rf 0.23 (EtOAc).

EXAMPLE 4 1-Propyl-4-(3-trifluoromethyl-phenyl)-piperidine

Beginning with 4-(3-Trifluoromethyl-phenyl)-piperidine and n-Pr-I: m.p.195° C. (HCl), MS m/z (rel. intensity, 70 eV) 271 (M+, 4), 243 (16), 242(bp), 159 (13), 70 (49).

EXAMPLE 5 1-Butyl-4-(3-trifluoromethyl-phenyl)-piperidine

Beginning with 4-(3-Trifluoromethyl-phenyl)-piperidine and n-Bu-Br: m.p.222° C. (HCl), MS m/z (rel. intensity, 70 eV) 285 (M+, 3), 243 (12), 242(bp), 70 (51), 56 (17).

EXAMPLE 6 4-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine

m.p. 200° C. (HCl) MS m/z (relative intensity, 70 eV) 281 (M+, 5), 252(bp), 129 (20), 115 (20), 70 (25.

EXAMPLE 74-(3-Methanesulfonyl-phenyl)-1-propyl-1,2,3,6-tetrahydro-pyridine

Beginning with 4-(3-methanesulfonyl-phenyl)-1,2,3,6-tetrahydro-pyridineand iodopropane: MS m/z (relative intensity, 70 eV) 279 (M+, 26), 250(bp), 171 (6), 128 (12), 115 (8).

EXAMPLE 8 4-(3-Methanesulfonyl-phenyl)-1-ethyl-piperidine

Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and iodoethane:m.p. 158° C. (HCl). MS m/z (rel. intensity, 70 eV) 267 (M+, 20), 252(bp), 130 (10), 115 (12), 84 (20);

EXAMPLE 9 1-Isopropyl-4-(3-methanesulfonyl-phenyl)-piperidine

Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine andi-propylbromide: m.p. 220° C. (HCl); MS m/z (rel. intensity, 70 eV) 281(M+, 4), 266 (bp), 187 (5), 129 (5), 115 (5)

EXAMPLE 10 4-(3-Methanesulfonyl-phenyl)-1-butyl-piperidine

Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and n-BuCl. MSm/z (rel. intensity, 70 eV) 295 (M+, 3), 252 (bp), 130 (5), 115 (3), 70(8).

EXAMPLE 11 1-Isobutyl-4-(3-methanesulfonyl-phenyl)-piperidine

Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine andi-butylbromide; m.p. 212° C. (HCl); MS m/z (rel. intensity, 70 eV) 295(M+, 1), 252 (80), 129 (40), 115 (50), 70 (bp).

EXAMPLE 12 3-(1-Propyl-piperidin-4-yl)-benzonitrile

A solution of 3-(1-propyl-piperidin-4-yl)-benzamide (350 mg) and POCl₃(326 μL) in dry DMF (6 ml) was heated at 80° C. for 3 h under an argonatmosphere. Evaporation of the solvent yielded a dark, oily residue,which was dissolved in water. The solution was basified and extractedwith CH₂Cl₂. The combined organic phases were dried (MgSO₄), filteredand evaporated. The oily residue was chromathographed on a silica columnwith MeOH:CH₂Cl₂ (1:19 (v/v)) as eluent. Collection of the fractionscontaining pure product and evaporation of the solvent afforded pure3-(1-Propyl-piperidin-4-yl)-benzonitrile (127 mg). The amine wasconverted into the fumarate salt and recrystallized fromethanol/diethylether: m.p. 122° C.; MS m/z (relative intensity, 70 eV)228 (M+, 2), 199 (42), 129 (26), 70 (bp) 56 (53).

EXAMPLE 13 1-sec-Butyl-4-(3-methanesulfonyl-phenyl)-piperidine

4-(3-methanesulfonyl-phenyl)-piperidine hydrochloride (20 mg), glacialacetic acid (4.4 mg) and 2-butanone (5.1 mg) were mixed in1,2-dichloroethane (5 mL). Sodium triacetoxyborohydride (23.5 mg) wasadded to the solution and the reaction mixture was stirred at roomtemperature under a nitrogen atmosphere for 5 h (G.L.C. analysisindicated a complete reaction). The reaction was quenched with saturatedaqueous NaHCO₃ and the product was extracted with CH₂Cl₂. The combinedorganic phases were dried (MgSO₄), filtered, and the solvent wasevaporated to afford 1-sec-butyl-4-(3-methanesulfonyl-phenyl)-piperidineas an oily residue. The product was chromatographed on a silica columnwith CH₂Cl₂:MeOH (9:1 (v/v)) as eluent. Collection of the fractionscontaining pure product and evaporation of the solvent afforded pureamine (15 mg, 71%); MS m/z (relative intensity, 70 eV) 295 (M+, 1), 280(7), 266 (bp), 187 (4), 129 (4).

EXAMPLE 14 Methanesulfonic acid 3-(1-propyl-piperidin-4-yl)-phenyl ester

A solution of 3-(1-propyl-piperidin-4-yl)-phenol (340 mg) andtriethylamine (187 mg) in 20 ml of CH₂Cl₂ was cooled to 0° C. Thenmethanesulfonyl chloride (194 mg) dissolved in 10 ml of CH₂Cl₂ was addeddropwise. The reaction mixture was allowed to reach room temperature andthen stirred for 2.5 h at 25° C. The reaction was finally quenched withwater. The organic layer was separated and washed with 10% HCl and then10% Na₂CO₃.

After drying (MgSO₄) the solvent was removed under reduced pressure. Theresidue was chromathographed on a silica column using MeOH:CH₂Cl₂ (1:9(v/v)) as eluent. The fractions containing pure methanesulfonic acid3-(1-propyl-piperidin-4-yl)-phenyl ester were collected, and the solventwas removed in vacuum, affording 206 mg of the title compound. (MS m/z(rel. intensity, 70 eV) 297 (M+, 3), 268 (bp), 189 (24), 131 (13), 79(16);

The following compounds in Examples 15-19 were prepared in a mannersimilar to the one described in Example 14.

EXAMPLE 15 Methanesulfonic acid 3-(1-ethyl-piperidin-4-yl)-phenyl ester

Beginning with 3-(1-ethyl-piperidin-4-yl)-phenol and methanesulfonylchloride. MS m/z (rel. intensity, 70 eV) 283 (M+, 6), 268 (bp), 189(54), 131 (20), 79 (70);

EXAMPLE 16 Methanesulfonic acid 3-(1-butyl-piperidin-4-yl)-phenyl ester

Beginning with 3-(1-butyl-piperidin-4-yl)-phenol and methanesulfonylchloride. MS m/z (rel. intensity, 70 eV) 311 (M+, 3), 268 (bp), 189(20), 131 (18), 79 (12);

EXAMPLE 17 Methanesulfonic acid 3-(4-propyl-piperazin-1-yl)-phenyl ester

Beginning with 3-(4-propyl-piperazin-1-yl)-phenol and methanesulfonylchloride: m.p 143-144° C. (fumarate); MS m/z (rel. intensity, 70 eV) 298(M+, 35), 269 (95), 121 (25), 84 (30), 70 (bp);

EXAMPLE 18 Trifluoro-methanesulfonic acid3-(1-propyl-piperidin-4-yl)-phenyl ester

Beginning with 3-(1-propyl-piperidin-4-yl)-phenol and triflic anhydrideMS m/z (rel. intensity, 70 eV) 351 (M+, 4), 322 (65), 189 (30), 131(20), 69 (bp).

EXAMPLE 19 Trifluoro-methanesulfonic acid3-(1-ethyl-piperidin-4-yl)-phenyl ester

Beginning with 3-(1-ethyl-piperidin-4-yl)-phenol and triflic anhydride:MS m/z (rel. intensity, 70 eV) 337 (M+, 4), 322 (65), 189 (30), 131(20), 69 (bp).

EXAMPLE 20 1-[3-(1-Propyl-piperidin-4-yl)-phenyl]-ethanone

To a stirred solution of trifluoro-methanesulfonic acid3-(1-propyl-piperidin-4-yl)-phenyl ester (300 mg) in DMF (4 ml) underargon atm at r.t. was subsequently added NEt₃ (356 μL), butyl vinylether (823 μL), 1,3-bis(diphenylphosphino)propane (50 mg), and Pd(OAc)₂(19 mg). The reaction mixture was then heated to 80° C. and after 2 hthe reaction was stopped. 5% Hydrochloric acid solution (6 ml) was addedand the combined mixture stirred for 45 min. Then CH₂Cl₂ was added andthe phases were separated. The aqueous layer was then extracted withCH₂Cl₂. The combined organic phases were dried (MgSO₄), filtered andevaporated to dryness. The crude product was purified by flashchromatography (MeOH:CH₂Cl₂ (1:9 (v/v)). Collection of the fractionscontaining pure product and evaporation of the solvent afforded pure1-[3-(1-Propyl-piperidin-4-yl)-phenyl]-ethanone (35 mg). MS m/z (rel.intensity, 70 eV) 245 (M+, 4), 216 (bp), 100 (19), 70 (36), 57 (13).

EXAMPLE 211-Propyl-4-(3-trifluoromethylsulfonylphenyl)-1,2,3,6-tetrahydropyridine

4-(3-Trifluoromethylsulfonylphenyl)-Pyridine (0.3 g) was dissolved in1-iodo-propane (2 ml) and heated to 100° C. for 2 h. Then the voilatileswere evaporated and the residue redissolved in abs EtOH (20 ml) andNaBH₄ (340 mg) was addded portions wise at −20° C. The mixture was thenallowed to reach r.t. and stirred over night. To the mixture was added10% Na₂CO₃ solution (20 ml). The aqueous layer was extracted with CH₂Cl₂and the combined organic phases were dried (MgSO₄), filtered andevaporated to dryness. The crude product was purified by flashchromatography (MeOH:CH₂Cl₂ (1:9 (v/v)) Collection of the fractionscontaining pure product and evaporation of the solvent afforded pure1-propyl-4-(3-trifluoromethyl-sulfonylphenyl)-1,2,3,6-tetrahydropyridine(150 mg). MS m/z (rel. intensity, 70 eV) 333 (M+, 21), 305 (16), 304(bp), 171 (14), 128 (14). Rf 0.55 (MeOH)

EXAMPLE 22 1-Propyl-4(3-trifluoromethylsulfonylphenyl)-piperidine

Beginning with1-propyl-4-(3-trifluoromethyl-sulfonyl-phenyl)-1,2,3,6-tetrahydropyridine,1-Propyl-4(3-trifluoro-methylsulfonylphenyl)-piperidine was recovered bythe procedure described in Preparation 9. MS m/z (relative intensity, 70eV) 335 (M+, 3), 307 (17), 306 (bp), 173 (26), 70 (10).

EXAMPLE 23 1-Allyl-4-(3-methanesulfonyl-phenyl)-piperidine

Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and allylbromide,the titled compound was recovered by the procedure described inExample 1. MS m/z (relative intensity, 70 eV) 279 (M+, 74), 96 (bp), 82(98), 68 (74), 55 (93). Rf=0.42 (MeOH, 0.08 (EtOAc).

EXAMPLE 244-(3-Methanesulfonyl-phenyl)-1-(tetrahydro-furan-2-ylmethyl)-piperidine

Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine andtetrahydrofurfuryl chloride, the titled compound was recovered by theprocedure described in Example 1. MS m/z (relative intensity, 70 eV) 323(M+, 1), 252 (bp), 129 (9), 115 (6), 70 (17). Rf=0.3 (MeOH, 0.03(EtOAc).

Syntheses of intermediates used in the above Examples are described inthe preparations below.

PREPARATION 14-Hydroxy-4-(3-methylsulfanyl-phenyl)-piperidin-1-carboxylic acidtert-butyl ester

1-Bromo-3-methylsulfanyl-benzene (5.0 g, 24.6 mmol) was dissolved in dryTHF (40 ml) and cooled to −78° C. under a stream of Argon (g). n-BuLi(12.8 ml, 2.5 M in hexane, 31.9 mmol) was added dropwise via syringe andthe reaction mixture was stirred for an additional 30 min at −78° C.,then the temperature was increased to 0° C. for 5 min and then decreasedto −78° C. 1-tert-Butoxycarbonyl-4-piperidone (5.4 g, 27.06 mmol)dissolved in dry THF (30 ml) was added via syringe. The reaction mixturewas allowed to reach room temperature and then stirred for 1 hour, andfinally quenched with saturated ammonium chloride solution (30 ml). Themixture was extracted several times with EtOAc and the combined organicphases were dried (MgSO₄), filtered and evaporated to dryness. The oilyresidue was chromatho-graphed on a silica column using CH₂Cl₂:MeOH (19:1(v/v)) as eluent, yielded4-hydroxy-4-(3-methylsulfanyl-phenyl)-piperidin-1-carboxylic acidtert-butyl ester (6 g, 76%). MS m/z (relative intensity, 70 eV) 323.1(M+, 6), 223.0 (11), 178.0 (7), 152 (3), 57.0 (bp), 56 (30).

PREPARATION 2 1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-ol

Beginning with 3-bromoanisole (5 g) and 1-benzyl-4-piperidone (5.5 g),4.58 g of 1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-ol was recovered bythe procedure described in Preparation 1. MS m/z (relative intensity, 70eV) 297 (M+, 8), 279 (13), 206 (28), 146 (17), 91 (bp).

PREPARATION 3 1-Benzyl-4-(3-trifluoromethyl-phenyl)-piperidin-4-ol

Beginning with 3-trifluoromethyl-iodobenzene (3 g) and1-benzyl-4-piperidone (2.1 g), 1.75 g of the title compound wasrecovered by the procedure described in preparation 1. MS m/z (rel.intensity, 70 eV) 335 (M+, 29), 244 (22), 146 (19), 91 (bp), 56 (19).

PREPARATION 4 4-(3-Methylsulfanyl-phenyl)-1,2,3,6-tetrahydro-pyridine

4-Hydroxy-4-(3-methylsulfanyl-phenyl)-piperidin-1-carboxylic acidtert-butyl ester (3.97 g) was dissolved in CH₂Cl₂ (500 ml) andtrifluoroacetic acid (80 ml) was added in one portion. The mixture wasrefluxed for one hour and then washed with two portions of 10%-Na₂CO₃,dried (MgSO₄), filtered and evaporated to dryness. Yield 2.07 g. MS m/z(relative intensity, 70 eV) 205 (M+, 73), 158 (44), 129 (95), 128 (80),82 (bp).

PREPARATION 5 1-Benzyl-4-(3-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridine

Beginning with 1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-ol (4.5 g) andtrifluoroacetic acid (80 ml), 3.5 g of1-benzyl-4-(3-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridine was recoveredby the procedure described in Preparation 4. MS m/z, (relativeintensity, 70 eV) 279 (M+, 35), 145 (13), 115 (15), 91 (bp) 65 (22).

PREPARATION 61-Benzyl-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine

Beginning with 1-Benzyl-4-(3-trifluoromethyl-phenyl)-piperidin-4-ol(1.74 g), 1.44 g of the title compound was recovered by the proceduredescribed in preparation 4 (neat CF₃COOH). MS m/z (rel. intensity, 70eV) 317 (M+, 71), 226 (13), 172 (15), 91 (bp), 65 (17).

PREPARATION 74-(3-Methylsulfanyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidmethyl ester

4-(3-Methylsulfanyl-phenyl)-1,2,3,6-tetrahydro-pyridine (2 g) and NEt3(1 g) were dissolved in CH₂Cl₂ (75 ml) and cooled to 0° C. Methylchloroformate (0.96 g) dissolved in CH₂Cl₂ (20 ml) was added dropwiseand the reaction mixture was then allowed to reach room temperature.After an additional two hours at room temperature the reaction mixturewas washed with 10% Na₂CO₃ solution, dried (MgSO4), filtered andconcentrated by evaporation. The oily residue was chromatographed on asilica column using CH₂Cl₂:MeOH (19:1 (v/v)) as eluent,4-(3-methylsulfanyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidmethyl ester (1.4 g). MS m/z (relative intensity, 70 eV) 263 (M+ 45),248 (89), 129 (83), 128 (bp), 59 (96).

PREPARATION 84-(3-Methanesulfonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidmethyl ester

4-(3-Methylsulfanyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidmethyl ester (1.4 g) was dissolved in CH₂Cl₂ (150 ml) and cooled to 0°C. m-Chloroperoxybenzoic acid (2.48 g) was added portions wise and themixture was stirred at room temperature for three hours. The resultingclear solution was washed with 10%-Na₂CO₃ solution, dried (MgSO₄),filtered and concentrated by evaporation and yielding an oily residue(1.3 g). MS m/z (relative intensity, 70 eV) 295 (M+, 19), 280 (56), 129(70), 128 (89), 59 (bp).

PREPARATION 9 4-(3-Methanesulfonyl-phenyl)-piperidin-1-carboxylic acidmethyl ester

4-(3-Methanesulfonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidmethyl ester (2.0 g) was dissolved in methanol (40 ml). Concentratedhydrochloric acid (2 ml) and Pd/C (500 mg) were added. The resultingmixture was hydrogenated under a hydrogen gas pressure (50 psi) for 8 hand then filtered through a pad of celite. The solvent was evaporated invacuum and the residue was purified by flash chromatography (CH₂Cl₂:MeOH, 3:1 (v/v)). Yield 0.92 g MS m/z (relative intensity, 70 eV) 297(M+, 54), 282 (62), 238 (bp), 115 (92), 56 (93).

PREPARATION 10 4-(3-Methoxy-phenyl)-piperidine

Beginning with 1-Benzyl-4-(3-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridine(5.1 g) and 900 mg Pd/C, 1.7 g of 4-(3-Methoxy-phenyl)-piperidine wasrecovered by the procedure described in Preparation 9. The oily residuewas purified by flash chromatography (SiO₂, CH₂Cl₂:MeOH, 3:1 (v/v) with1% NEt₃) to give the pure title compound. MS m/z (relative intensity, 70eV) 191 (M+, 75), 160 (60), 83 (55), 57 (80), 56 (bp)

PREPARATION 11 4-(3-Trifluoromethyl-phenyl)-piperidine

Beginning with1-Benzyl-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (1.44g), 1 g of the title compound as HCl salt was recovered by the proceduredescribed in preparation 9. m.p. 202° C. (HCl); MS m/z (rel. intensity,70 eV) 229 (M+, 44), 228 (33), 83 (12), 57 (54), 56 (bp).

PREPARATION 12 4-(3-Methanesulfonyl-phenyl-piperidine

4-(3-Methanesulfonyl-phenyl)-piperidin-1-carboxylic acid methyl ester(0.92 g) dissolved in ethanol (15 ml) and 8 M HCl (40 ml) was refluxedfor 12 hours. The mixture was then evaporated in vacuum to dryness.Yield 0.85 g MS m/z (relative intensity, 70 eV) 239 (M+, 59), 238 (50),69 (20), 57 (79),56 (bp).

PREPARATION 13 3-Piperidin-4-yl-phenol

4-(3-Methoxy-phenyl)-piperidine (1.7 g) was dissolved in 48-% HBr (60ml) and stirred at 120° C. under an Argon-atmosphere for 3 h. The excessof HBr was then evaporated and absolute ethanol added and evaporated.This procedure was repeated several times to yield dry crystals of3-piperidin-4-yl-phenol×HBr (2.3 g). MS m/z (relative intensity, 70 eV)177 (M+, bp), 176 (23), 91 (14), 57 (44), 56 (60).

PREPARATION 14 3-(1-Propyl-piperidin-4-yl)-phenol×HBr

Beginning with 3-piperidin-4-yl-phenol×HBr (300 mg) and n-propyl iodide(200 mg), 340 mg of 3-(1-propyl-piperidin-4-yl)-phenol was recovered bythe procedure described in Example 1. The HBr salt was prepared toprovide the title compound. MS m/z (rel. intensity, 70 eV) 219 (M+, 21),190 (bp), 119 (22), 91 (30), 70 (63); m.p. 181-184° C. (HBr).

PREPARATION 15 3-(1-Ethyl-piperidin-4-yl)-phenol

Beginning with 3-piperidin-4-yl-phenol×HBr (200 mg) and Ethyl iodide(121 mg), 120 mg of 3-(1-ethyl-piperidin-4-yl)-phenol was recovered bythe procedure described in Example 1. MS m/z (rel. intensity, 70 eV) 205(M+, 12), 190 (bp), 119 (36), 91 (22), 70 (87).

PREPARATION 16 3-(1-Butyl-pieridin-4-yl)-phenol

Beginning with 3-piperidin-4-yl-phenol×HBr (200 mg) and n-butyl chloride(73 mg), 118 mg of 3-(1-butyl-piperidin-4-yl)-phenol was recovered bythe procedure described in Example 1. MS m/z (rel. intensity, 70 eV) 233(M+, 6), 190(bp), 119 (42), 91 (26), 70 (45).

PREPARATION 17 1-(3-Methanesulfonyl-phenyl)-piperazine

A mixture of 1-bromo-3-methanesulfonyl-benzene (0.8 g), piperazine (1g), sodium tert-butoxide (0.5 g) BINAP (42 mg) and [Pd₂(dba)₃ (38 mg) intoluene (7 ml) was heated under argon at 80° C. for 24 h. After coolingto room temperature, the solvent was evaporated to dryness. The crudematerial was purified by flash chromatography on silica gel using EtOAc.Yield 0.48 g: MS m/z (rel. intensity, 70 eV) 240 (M+, 17), 199 (12), 198(bp), 119 (9), 56 (7).

PREPARATION 18 1-(3-Trifluoromethanesulfonyl-phenyl)-piperazine

Beginning with 3-bromo-trifluoromethanesulfonyl-benzene and piperazine,the titled cmp was recovered by the procedure described in Preparation17. MS m/z (rel. intensity, 70 eV) 294 (M+, 22), 252 (bp), 119 (32), 104(10), 56 (15). (45).

PREPARATION 19 1-(3-Piperazin-1-yl-phenyl)-ethanone

Beginning with 3-bromo-acetophenone and piperazine, the titled cmp wasrecovered by the procedure described in Preparation 17. MS m/z (rel.intensity, 70 eV) 204 (M+, 5), 162 (35), 77 (30), 57 (35), 56 (bp)

PREPARATION 20 3-(1-Propyl-piperidin-4-yl)-benzoic acid methyl ester

A mixture of trifluoro-methanesulfonic acid3-(1-propyl-piperidin-4-yl)-phenyl ester (1.2 g), triethyl amine (0.9g), MeOH (5.4 ml), Pd(OAc)₂ (25 mg) and1,3-bis(di-phenyl-phosphino)propane (45 mg) in 15 ml DMSO was stirred atroom temperature for 15 min. A stream of CO (g) was passed through thesolution for 4-5 min., and then the reaction vessel was placed under asligthly positive pressure of CO (g). The temp was increased to 70° C.After 6 h the reaction was allowed to cool to r.t. Water was then added,and the aqueous solution was extracted with five portions of ethylacetate and the combined organic phases were dried (MgSO₄), andevaporated. The residue was chromathographed on a silica column usingMeOH: CH₂Cl₂ (1:9 (v/v)) as eluent. The fractions containing pure titledcompound were collected, and the solvent was removed in vacuum,affording 650 mg of the titled compound. (MS m/z (rel. intensity, 70 eV)261 (M+, 5), 233 (16), 232 (bp), 161 (5), 70 (20)

PREPARATION 21 3-(1-Propyl-piperidin-4-yl)-benzamide

A solution of 3-(1-Propyl-piperidin-4-yl)-benzoic acid methyl ester (0.6g) and formamide (320 μL) in DMF (9 ml) was heated to 100° C. under ablanket of argon. Sodium methoxide in methanol (30%, 770 μL) was addeddropwise and after 1 h, GC analysis revealed the complete absence ofstarting material and indicated the titled compound as the sole product.After cooling, CH₂Cl₂ was added and the resulting solution was filteredthrough a pad of celite and evaporated to dryness. The residue waschromathographed on a silica column using MeOH: CH₂Cl₂ (1:3 (v/v)) aseluent. The fractions containing pure titled compound were collected,and the solvent was removed in vacuum, affording 400 mg of the titledcompound. m.p. 182° C. (oxalate) (MS m/z (rel. intensity, 70 eV) 246(M+, 4), 217 (bp), 131 (19), 100 (22), 70 (63).

PREPARATION 22 4-(3-Trifluoromethylsulfonyl-phenyl)-pyridine

1-Bromo-3-trifluoromethylsulfonyl benzene (580 mg) and4-pyridine-boronic acid (275 mg) was dissolved in toluene (5 ml) and absEtOH (5 ml). To the mixture was then added Na₂CO₃ (424 mg) and Pd(PPh₃)₄(119 mg) under an atmosphere of Argon. The resulting mixture was heatedto 90° C. for 18 h. Then CH₂Cl₂ was added and the organic phase waswashed with water and dried (MgSO₄), filtered and evaporated to dryness.The residue was then used without any further purification. (MS m/z(rel. intensity, 70 eV) 287 (M+, 33), 218 (22), 154 (bp), 127 (56), 69(27).

The following tests were used for evaluation of the compounds accordingto the invention.

In Vivo Test: Behavior

For behavioral testing, the animals were placed in separate motilitymeter boxes 50×50×50 cm equipped with an array of 16×16 photocells(Digiscan activity monitor, RXYZM (16) TAO, Omnitech Electronics, USA),connected to an Omnitech Digiscan analyzer and a Apple Macintoshcomputer equipped with a digital interface board (NB DIO-24, NationalInstruments, USA). Behavioral data from each motility meter box,representing the position (center of gravity) of the animal at eachtime, were recorded at a sampling frequency of 25 Hz and collected usinga custom written LABView™ application. The data from each recordingsession were analyzed with respect to distance traveled and small-scalemovements, e.g. stops in the center of the behavior recording arena,during the recording session. To determine stops in the center, velocityat each time point is calculated as the distance traveled since thepreceding sample divided by the time elapsed since the preceding sample.The number of stops is then calculated as the number of times that thevelocity changes from a non-zero value to zero. The number of stops inthe center of the behavioral recording arena is calculated as the numberof stops occurring at a position at least ten centimeters from the edgesof the recording arena. For behavioral testing of habituated rats, theanimals were placed in the motility meter boxes 30 minutes before theadministration of test compound. Each behavioral recording sessionlasted 6 or 30 minutes, starting immediately after the injection of testcompound. Similar behavioral recording procedures was applied fornon-habituated rats, habituated rats and drug pre-treated rats. Ratspre-treated with d-amphetamine are given the dose 1,5 mg/kg s.c. 5 minbefore the behavioral session in the motility meter. Rats pre-treatedwith dizolcipine (Mk-801) are given the dose 0,7 mg/kg i.p. 90 minbefore the behavioral session.in the motility meter.

In Vivo Test: Neurochemistry

After the behavioral activity sessions the rats were decapitated andtheir brains rapidly taken out and put on an ice-cold petri-dish. Thelimbic forebrain, the striatum, the frontal cortex and the remaininghemispheral parts of each rat were dissected and frozen. Each brain partwas subsequently analyzed with respect to its content of monoamines andtheir metabolites. The monoaminergic indices analyzed were dopamine(DA), 3,4-dihydroxy-phenylacetic acid (DOPAC), homovanillic acid (HVA),3-methoxytyramine (3-MT), serotonin (5-HT), 5-hydroxyindole acetic acid(5-HIAA), and noradrenaline (NA). All monoaminergic indices in thedissected tissue were analyzed by means of HPLC with electrochemicaldetection as described by Svensson K, et al., 1986,Naunyn-Schmiedeberg's Arch Pharmacol 334: 234-245 and references citedtherein.

In Vivo Test: Pharmacokinetics in the Rat

To determine oral availability (F) and plasma half life (t½) of testcompounds according to the invention experiments performed in the ratwere undertaken. On day one rats were implanted with one catheter in thejugular vein and one catheter in the carotid artery under ketamineanesthesia. On day three test compound is injected either orally or inthe jugular vein catheter. Blood samples are collected during 8 hoursfrom the arterial catheter. The blood samples were heparinized andcentrifuged. Plasma is collected from the centrifuged samples andfrozen. The levels of test compound were subsequently determined in eachsample by means of gas chromatography-mass spectrometry (Hewlett-Packard5972MSD). The plasma samples, taken from the rats of the Sprague-Dawleystrain, (0.5 ml) were diluted with water (0.5 ml), and 30 pmol (50 μl)of ((−)-S-3-(3-Ethylsulfonylphenyl)-N-n-propyl-piperidine as internalstandard was added. The pH was adjusted to 11.0 by the addition of 25 μlsaturated Na₂CO₃. After mixing, the samples were extracted with 4 mldichloromethane by shaking for 20 min. The organic layer was, aftercentrifugation, transferred to a smaller tube and evaporated to drynessunder a stream of nitrogen and subsequently redissolved in 40 μl toluenefor GC-MS analysis. A standard curve over the range of 1-500 μmol wasprepared by adding appropriate amounts of test compound to blank plasmasamples. GC was performed on a HP-Ultra 2 capillary column (12 m×0.2 mmID), and 2 μl was injected in the splitless mode. The GC temperature washeld at 90° C. for 1 minute following injection, and was then increasedby 30° C./min to the final temperature of 290° C. Each sample was run induplicate. The lowest detectable concentration of test compound wasgenerally found to be 1 pmol/ml.

1. A 4-(phenyl-N-alkyl)-piperidine compound of Formula 1:

wherein: R₁ is selected from the group consisting of OSO₂CF₃, OSO₂CH₃,SOR₃, SO₂R₃, COCH₃, and COCH₂CH₃, wherein R₃ is as defined below; R₂ isselected from the group consisting of C₂-C₄ branched or unbranchedalkyls, terminal allyl, CH₂CH₂OCH₃, CH₂CH₂CH₂F, CH₂CF₃,3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl, R₃ is selected from thegroup consisting of C₁-C₃ alkyls, CF₃, and N(CH₃)₂; or apharmaceutically acceptable salt thereof, wherein the compound does nothave a high binding affinity to sigma receptors.
 2. A compound accordingto claim 1, wherein R₁ is selected from the group consisting of OSO₂CF₃,OSO₂CH₃, SO₂CH₃, SO₂CF₃, COCH₃, and SO₂N(CH₃)₂.
 3. A compound accordingto claim 2, wherein R₁ is selected from the group consisting of SO₂CF₃,SO₂CH₃, and COCH₃.
 4. A compound according to claim 1, wherein R₂ isselected from the group consisting of n-propyl and ethyl.
 5. A compoundaccording to claim 1, wherein said compound is4-(3-methanesulfonylphenyl)-1-propyl-piperidine.
 6. A pharmaceuticalcomposition comprising a compound according to claim 1 and one or morepharmaceutically acceptable carriers or diluants.
 7. The pharmaceuticalcomposition according to claim 6, wherein the pharmaceutical compositionis formulated for oral administration.
 8. The pharmaceutical compositionaccording to claim 7, wherein said pharmaceutical composition isformulated as a tablet.
 9. The pharmaceutical composition according toclaim 7, wherein said pharmaceutical composition is formulated as acapsule.
 10. The pharmaceutical composition according to claim 6,formulated for intravenous (i.v.) administration.
 11. A method fortreatment of a patient suffering from a condition selected from thegroup consisting of iatrogenic and non-iatrogenic Parkinsonism,dyskinesias, dystonias, and Tourette's disease, comprising administeringa therapeutically active amount of a compound according to claim 1 tosaid patient.
 12. A method for treatment of a patient suffering from acondition selected from the group consisting of iatrogenic andnon-iatrogenic psychoses and hallucinoses, comprising administering atherapeutically active amount of a compound according to claim 1 to saidpatient.
 13. A method for treatment of a patient suffering from acondition selected from the group consisting of mood and anxietydisorders, comprising administering a therapeutically active amount of acompound according to claim 1 to said patient.
 14. A method fortreatment of a patient suffering from a sleep disorder, comprisingadministering a therapeutically active amount of a compound according toclaim 1 to said patient.
 15. A method for treatment of a patientsuffering from a condition selected from the group consisting of autismspectrum disorder, ADHD, Huntington's disease and age-related cognitiveimpairment, comprising administering a therapeutically active amount ofa compound according to claim 1 to said patient.
 16. A method fortreatment of a patient suffering from a disorder related to abuse ofalcohol and substances used as narcotics, comprising administering atherapeutically active amount of a compound according to claim 1 to saidpatient.
 17. The method according to claim 12, wherein thenon-iatrogenic psychoses and hallucinoses are schizophrenia orschizophreniform disorders.
 18. The method according to claim 13,wherein the mood and anxiety disorder is manodepressive illness,depression or obsessive-compulsive disease.
 19. A method for treatmentof a patient suffering from Parkinson's disease, comprisingadministering a therapeutically active amount of a compound according toclaim 1 to said patient.
 20. A method for treatment of a patientsuffering from a condition selected from the group consisting ofiatrogenic and non-iatrogenic Parkinsonism, dyskinesias, dystonias, andTourette's disease comprising administering a therapeutically activeamount of a compound according to claim 5 to said patient.
 21. A methodfor treatment of a patient suffering from a condition selected from thegroup consisting of iatrogenic and non-iatrogenic psychoses andhallucinoses, comprising administering a therapeutically active amountof a compound according to claim 5 to said patient.
 22. A method fortreatment of a patient suffering from a condition selected from thegroup consisting of mood and anxiety disorders, comprising administeringa therapeutically active amount of a compound according to claim 5 tosaid patient.
 23. A method for treatment of a patient suffering from asleep disorder, comprising administering a therapeutically active amountof a compound according to claim 5 to said patient.
 24. A method fortreatment of a patient suffering from a condition selected from thegroup consisting of autism spectrum disorders, ADHD, Huntington'sdisease and age-related cognitive impairment, comprising administering atherapeutically active amount of a compound according to claim 5 to saidpatient.
 25. A method for treatment of a patient suffering from adisorder related to abuse of alcohol and substances used as narcotics,comprising administering a therapeutically active amount of a compoundaccording to claim 5 to said patient.
 26. The method according to claim21, wherein the non-iatrogenic psychoses and hallucinoses areschizophenia or schizophreniform disorders.
 27. The method according toclaim 22, wherein the mood and anxiety disorder is manodepressiveillness, depression or obsessive-compulsive disease.
 28. A method fortreatment of a patient suffering from Parkinson's disease, comprisingadministering a therapeutically active amount of a compound according toclaim 5 to said patient.
 29. A method for treatment of a patientsuffering from a condition selected from the group consisting ofiatrogenic and non-iatrogenic Parkinsonism, dyskinesias, dystonias, andTourette's disease, comprising administering a therapeutically activeamount of a pharmaceutical composition according to claim 6 to saidpatient.
 30. A method for treatment of a patient suffering from acondition selected from the group consisting of iatrogenic andnon-iatrogenic psychoses and hallucinoses, comprising administering atherapeutically active amount of a pharmaceutical composition accordingto claim 6 to said patient.
 31. A method for treatment of a patientsuffering from a condition selected from the group consisting of moodand anxiety disorders, comprising administering a therapeutically activeamount of a pharmaceutical composition according to claim 6 to saidpatient.
 32. A method for treatment of a patient suffering from a sleepdisorder, comprising administering a therapeutically active amount of apharmaceutical composition according to claim 6 to said patient.
 33. Amethod for treatment of a patient suffering from a condition selectedfrom the group consisting of autism spectrum disorder, ADHD,Huntington's disease and age-related cognitive impairment, comprisingadministering a therapeutically active amount of a pharmaceuticalcomposition according to claim 6 to said patient.
 34. A method fortreatment of a patient suffering from a disorder related to abuse ofalcohol and substances used as narcotics, comprising administering atherapeutically active amount of a pharmaceutical composition accordingto claim 6 to said patient.
 35. The method according to claim 30,wherein the non-iatrogenic psychoses and hallucinoses are schizophreniaor schizophreniform disorders.
 36. The method according to claim 31,wherein the mood and anxiety disorder is manodepressive illness,depression or obsessive-compulsive disease.
 37. A method for treatmentof a patient suffering from Parkinson's disease, comprisingadministering a therapeutically active amount of a pharmaceuticalcomposition according to claim 6 to said patient.